The present invention, in general, relates to ester derivatives and amide derivatives of various drugs, more specifically, such derivatives of non-steroidal antiinflammatory drugs (NSAIDs). Even more specifically, the present invention relates to ester derivatives and secondary amide derivatives of NSAIDs, particularly of indomethacin (an NSAID), that exhibit inhibition of cyclooxygenase-2(COX-2) far exceeding inhibition of cyclooxygenase-1(COX-1), and also, that still exhibit the analgesic, antiinflammatory, and/or antipyretic effect of the NSAID, in warm blooded vertebrate animals, including humans.
As discussed in more detail below, the COX enzyme is really two enzymes, COX-1 and COX-2, which serve different physiological and pathophysiological functions. As is well known, at antiinflammatory and/or analgesic doses, indomethacin, aspirin, and other NSAIDs effect great inhibition of COX-1, which protects the lining of the stomach from acid, along with relatively minimal inhibition of COX-2, which provokes inflammation in response to joint injury or a disease like arthritis. Also, certain NSAIDs exhibit essentially the same inhibitory activity against both COX-1 and COX-2. Thus, zeroing in on inhibition of COX-2 alone has been the goal of drug developers for several years in order to reduce or eliminate the GI irritation caused by COX-1 inhibition.
More specifically, as discussed in Smith, Garavito, and DeWitt, xe2x80x9cD. L. Prostaglandin Endoperoxide H Synthases (Cyclooxygenases)-1 and -2xe2x80x9d, J. Biol. Chem., (1996) Vol. 271, pp. 33157-33160, the pertinent step in prostaglandin and thromboxane biosynthesis involves the conversion of arachidonic acid to PGH2, which is catalyzed by the sequential action of the COX and PER activities of PGHS, as set out in the following reaction scheme: 
That COX activity originates from two distinct and independently regulated enzymes, termed COX-1 and COX-2, is described in DeWitt and Smith, xe2x80x9cPrimary Structure of Prostaglandin G/H Synthase from Sheep Vesicular Gland Determined from the Complementary DNA Sequencexe2x80x9d, Proc. Natl. Acad. Sci. U.S.A. (1988) Vol. 85, pp. 1412-1416; Yokoyama and Tanabe, xe2x80x9cCloning of Human Gene Encoding Prostaglandin Endoperoxide Synthase and Primary Structure of the Enzymexe2x80x9d, Biochem. Biophys. Res. Commun. (1989) Vol. 165, pp. 888-894; and Hla and Neilson, xe2x80x9cHuman Cyclooxygenase-2-cDNAxe2x80x9d, Proc. Natl. Acad. Sci. U.S.A. (1992) Vol. 89, pp. 7384-7388.
COX-1 is the constitutive isoform and is mainly responsible for the synthesis of cytoprotective prostaglandins in the GI tract and for the synthesis of thromboxane, which triggers platelet aggregation in blood platelets. See, Allison, Howatson, Torrence, Lee, and Russell, xe2x80x9cGastrointestinal Damage Associated with the Use of Nonsteroidal Antiinflammatory Drugsxe2x80x9d, N. Engl. J. Med. (1992) Vol. 327, pp. 749-754.
On the other hand, COX-2 is inducible and short-lived. Its expression is stimulated in response toendotoxins, cytokines, and mitogens. See, Kujubu, Fletcher, Varnum, Lim, and Herschman, xe2x80x9cTIS10, A Phorbol Ester Tumor Promoter Inducible mRNA from Swiss 3T3 Cells, Encodes a Novel Prostaglandin Synthase/Cyclooxygenase Homologuexe2x80x9d, J. Biol. Chem. (1991) Vol. 266, pp. 12866-12872; Lee, Soyoola, Chanmugam, Hart, Sun, Zhong, Liou, Simmons, and Hwang, xe2x80x9cSelective Expression of Mitogen-Inducible Cyclooxygenase in Macrophages Stimulated with Lipopolysaccharidexe2x80x9d, J. Biol. Chem. (1992) Vol. 267, pp. 25934-25938; and O""Sullivan, Huggins, Jr., and Mccall, xe2x80x9cLipopolysaccharide-induced Expression of Prostaglandin H Synthase-2 in Aveolar Macrophages is Inhibited by Dexamethasone by not by Aspirinxe2x80x9d, Biochem. Biophys. Res. Commun. (1993) Vol. 191, pp. 1294-1300.
Importantly, COX-2 plays a major role in prostaglandin biosynthesis in inflammatory cells (monocytes/macrophages) and in the central nervous system. See, Masferrer, Zweifel, Manning, Hauser, Leahy, Smith, Isakson, and Seibert, xe2x80x9cSelective Inhibition of Inducible Cyclooxygenase-2 in vivo is Antiinflammatory and Nonulcerogenicxe2x80x9d, Proc. Natl. Acad. Sci. U.S.A. (1994) Vol. 91, pp. 3228-3232; Vane, Mitchell, Appleton, Tomlinson, Bishop-Bailey, Croxtall, and Willoughby, xe2x80x9cInducible Isoforms of Cyclooxygenase and Nitric Oxide Synthase in Inflammationxe2x80x9d, Proc. Natl. Acad. Sci. U.S.A. (1994) Vol. 91, pp. 2046-2050; Harada, Hatanaka, Saito, Majima, Ogino, Kawamura, Ohno, Yang, Katori, and Yamamoto, xe2x80x9cDetection of Inducible Prostaglandin H Synthase-2 in Cells in the Exudate of Rat Carrageenin-Induced Pleurisyxe2x80x9d, Biomed. Res. (1994) Vol. 15, pp. 127-130; Katori, Harada, Hatanaka, Kawamura, Ohno, Aizawai, and Yamamoto, xe2x80x9cInduction of Prostaglandin H Synthase-2 in Rat Carrageenin-Induced Pleurisy and Effect of a Selective COX-2 Inhibitorxe2x80x9d, Advances in Prostaglandin, Thromboxane, and Leukotriene Research (1995) Vol. 23, pp. 345-347; and Kennedy, Chan, Culp, and Cromlish, xe2x80x9cCloning and Expression of Rat Prostaglandin Endoperoxide Synthase (Cyclooxygenase-2) cDNAxe2x80x9d, Biochem. Biophys. Res. Commun. (1994) Vol. 197, pp. 494-500.
Hence, the differential tissue distribution of COX-1 and COX-2 provides a basis for the development of drugs that are selective COX-2 inhibitors (i.e., specificity for inhibition of COX-2 far exceeds inhibition of COX-1) as antiinflammatory, analgesic, and/or antipyretic agents with minimization of or without the GI and hematologic liabilities from COX-1 inhibition that plague most all currently marketed NSAIDs, most of which inhibit both COX-1 and COX-2, with specificity for COX-1 inhibition greatly exceeding that for COX-2 inhibition, although some have essentially similar inhibitory activity against both COX-1 and COX-2. See, for instance, Meade, Smith, and DeWitt, xe2x80x9cDifferential Inhibition of Prostaglandin Indoperoxide Synthase (Cyclooxygenase) Isozymes by Aspirin and Other Non-Steroidal Antiinflammatory Drugsxe2x80x9d, J. Biol. Chem., (1993) Vol. 268, pp. 6610-6614.
Detailed SAR studies have been reported for two general structural classes of selective COX-2 inhibitors (specificity for COX-2 inhibition far exceeds COX-1 inhibition) including certain acidic sulfonamides and certain diarylheterocyclics. The in vivo activities of these selective COX-2 inhibitors validate the concept that selective COX-2 inhibition is antiinflammatory and nonulcerogenic, as discussed in the following journal articles. Gans, Galbraith, Roman, Haber, Kerr, Schmidt, Smith, Hewes, and Ackerman, xe2x80x9cAnti-Inflammatory and Safety Profile of DuP 697, a Novel Orally Effective Prostaglandin Synthesis Inhibitorxe2x80x9d, J. Pharmacol. Exp. Ther. (1990) Vol. 254, pp. 180-187; Penning, Talley, Bertenshaw, Carter, Collins, Docter, Graneto, Lee, Malecha, Miyashiro, Rogers, Rogier, Yu, Anderson, Burton, Cogburn, Gregory, Koboldt, Perkins, Seibert, Veenhuizen, Zhang, and Isakson, xe2x80x9cSynthesis and Biological Evaluation of the 1,5-Diarylpyrazole Class of Cyclooxygenase-2 Inhibitors: Identification of 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, Celecoxib)xe2x80x9d, J. Med. Chem. (1997) Vol. 40, pp.1347-1365; Khanna, Weier, Yu, Xu, Koszyk, Collins, Koboldt, Veenhuizen, Perkins, Casler, Masferrer, Zhang, Gregory, Seibert, and Isakson, xe2x80x9c1,2-Diarylimidazoles as Potent Cyclooxygenase-2 Selective, and Orally Active Antiinflammatory Agentsxe2x80x9d, J. Med. Chem. (1997) Vol. 40, pp. 1634-1647; Khanna, Weier, Yu, Collins, Miyashiro, Koboldt, Veenhuizen, Curie, Siebert, and Isakson, xe2x80x9c1,2-Diarylpyrroles as Potent and Selective Inhibitors of Cyclooxygenase-2xe2x80x9d, J. Med. Chem. (1997) Vol. 40, pp. 1619-1633; Tsuji, Nakamura, Konishi, Tojo, Ochi, Senoh, and Matsuo, xe2x80x9cSynthesis and Pharmacological Properties of 1,5-Diarylyrazoles and Related Derivativesxe2x80x9d, Chem. Pharm. Bull. (1997) Vol. 45, pp. 987-995; Riendeau, Percival, Boyce, Brideau, Charleson, Cromlish, Ethier, Evans, Falgueyret, Ford-Hutchinson, Gordon, Greig, Gresser, Guay, Kargman, Lxc3xa9ger, Mancini, O""Neill, Quellet, Rodger, Thxc3xa9rien, Wang, Webb, Wong, Xu, Young, Zamboni, Prasit, and Chan, xe2x80x9cBiochemical and Pharmacological Profile of a Tetrasubstituted Furanone as a Highly Selective COX-2 Inhibitorxe2x80x9d, Br. J. Pharmacol. (1997) Vol. 121, pp.105-117; Roy, Leblanc, Ball, Brideau, Chan, Chauret, Cromlish, Ethier, Gauthier, Gordon, Greig, Guay, Kargman, Lau, O""Neill, Silva, Thxc3xa9rien, Van Staden, Wong, Xu, and Prasit, xe2x80x9cA New Series of Selective COX-2 Inhibitors: 5,6-Diarylthiazolo[3,2-b][1,2,4]-triazolesxe2x80x9d, Bioorg. Med. Chem. Lett. (1997) Vol.7, pp.57-62; Thxc3xa9rien, Brideau, Chan, Cromlish, Gauthier, Gordon, Greig, Kargman, Lau, Leblanc, Li, O""Neill, Riendeau, Roy, Wang, Xu, and Prasit, xe2x80x9cSynthesis and Biological Evaluation of 5,6-Diarylimidazo[2.1-b]thiazoles as Selective COX-2 Inhibitorsxe2x80x9d, Bioorg. Med. Chem. Lett. (1997) Vol.7, pp.47-52; Li, Norton, Reinhard, Anderson, Gregory, Isakson, Koboldt, Masferrer, Perkins, Seibert, Zhang, Zweifel, and Reitz, xe2x80x9cNovel Terphenyls as Selective Cyclooxygenase-2 Inhibitors and Orally Active Anti-Inflammatory Agentsxe2x80x9d, J. Med. Chem. (1996) Vol. 39, pp. 1846-1856; Li, Anderson, Burton, Cogburn, Collins, Garland, Gregory, Huang, Isakson, Koboldt, Logusch, Norton, Perkins, Reinhard, Seibert, Veenhuizen, Zhang, and Reitz, xe2x80x9c1,2-Diarylcyclopentenes as Selective Cyclooxygenase-2 Inhibitors and Orally Active Anti-Inflammatory Agentsxe2x80x9d, J. Med. Chem. (1995) Vol. 38, pp. 4570-4578; Reitz, Li, Norton, Reinhard, Huang, Penick, Collins, and Garland, xe2x80x9cNovel 1,2-Diarylcyclopentenes are Selective Potent and Orally Active Cyclooxygenase Inhibitorsxe2x80x9d, Med. Chem. Res. (1995) Vol. 5, pp. 351-363; Futaki, Yoshikawa, Hamasaka, Arai, Higuchi, lizuka, and Otomo, xe2x80x9cNS-398, A Novel Nonsteroidal Antiinflammatory Drug with Potent Analgesic and Antipyretic Effects, which Causes Minimal Stomach Lesionsxe2x80x9d, Gen. Phamacol. (1993) Vol.24, pp.105-110; Wiesenberg-Boetcher, Schweizer, Green, Muller, Maerki, and Pfeilschifter, xe2x80x9cThe Pharmacological Profile of CGP 28238, A Novel Highly Potent Anti-Inflammatory Compoundxe2x80x9d, Drugs Exptl Clin Res. (1989) Vol. XV, pp. 501-509; Futaki, Takahashi, Yokoyama, Arai, Higuchi, and Otomo, xe2x80x9cNS-398, A New Anti-Inflammatory Agent, Selectively Inhibits Prostaglandin G/H Synthase/Cyclooxygenase (COX-2) Activity in vitroxe2x80x9d, Prostaglandins (1994) Vol.47, pp.55-59; Klein, Nusing, Pfeilschifter, and Ullrich, xe2x80x9cSelective Inhibition of Cyclooxygenase-2xe2x80x9d, Biochem. Pharmacol. (1994) Vol. 48, pp. 1605-1610; Li, Black, Chan, Ford-Hutchinson, Gauthier, Gordon, Guay, Kargman, Lau, Mancini, Quimet, Roy, Vickers, Wong, Young, Zamboni, and Prasit, xe2x80x9cCyclooxygenase-2 Inhibitors. Synthesis and Pharmacological Activities of 5-Methanesulfonamido-1-indanone Derivativesxe2x80x9d, J. Med. Chem. (1995) Vol. 38, pp.4897-8905; Prasit, Black, Chan, Ford-Hutchinson, Gauthier, Gordon, Guay, Kargman, Lau, Li, Mancini, Quimet, Roy, Tagari, Vickers, Wong, Young, and Zamboni, xe2x80x9cL-745,337: A Selective Cyclooxygenase-2 Inhibitorxe2x80x9d, Med. Chem. Res. (1995) Vol. 5, pp. 364-374; Tanaka, Shimotori, Makino, Aikawa, Inaba, Yoshida, and Takano, xe2x80x9cPharmacological Studies of the New Antiinflammatory Agent 3-Formylamino-7-methylsulfonylamino-6-phenoxy4H-1-benzopyran4-one. 1st Communication: Antiinflammatory, Analgesic and Other Related Propertiesxe2x80x9d, Arzniem.-Forsch./Drug Res. (1992) Vol. 42, pp. 935-944; Nakamura, Tsuji, Konishi, Okumura, and Matsuo, xe2x80x9cStudies on Anti-Inflammatory Agents. I. Synthesis and Pharmacological Properties of 2xe2x80x2-(phenylthio)methanesulfonamides and Related Derivativesxe2x80x9d, Chem. Pharm. Bull. (1993) Vol. 41, pp. 894-906; Chan, Boyce, Brideau, Ford-Hutchinson, Gordon, Guay, Hill, Li, Mancini, Penneton, Prasit, Rasori, Riendeau, Roy, Tagari, Vickers, Wong, and Rodger, xe2x80x9cPharmacology of a Selective Cyclooxygenase-2 Inhibitor, L-745,337: A Novel Nonsteroidal Anti-Inflammatory Agent with an Ulcerogenic Sparing Effect in Rat and Nonhuman Primate Stomachxe2x80x9d, J. Pharmacol. Exp. Ther. (1995) Vol. 274, pp. 1531-1537; and Graedon and Graedon, xe2x80x9cPills Promise Relief without Ulcersxe2x80x9d, The Raleigh, North Carolina News and Observer, p. 8D (Sep. 13, 1998) which addresses, in general terms, the development of celecoxib, meloxicam, and vioxx as selective COX-2 inhibitors.
Representative acidic sulfonamides and diarylheterocyclics that have been reported as selective COX-2 inhibitors in the journal articles mentioned in the above paragraph are: 
Although acidic sulfonamides and diarylheterocyclics have been extensively studied as selective COX-2 inhibitors, there are very few reports on converting NSAIDs that are selective COX-1 inhibitors into selective COX-2 inhibitors. See, Black, Bayly, Belley, Chan, Charleson, Denis, Gauthier, Gordon, Guay, Kargman, Lau, Leblanc, Mancini, Quellet, Percival, Roy, Skorey, Tagari, Vickers, Wong, Xu, and Prasit, xe2x80x9cFrom Indomethacin to a Selective COX-2 Inhibitor: Development of Indolalkanoic Acids as Potent and Selective Cyclooxygenase-2 Inhibitorsxe2x80x9d, Bioorg. Med. Chem. Lett. (1996) Vol. 6, pp. 725-730; Luong, Miller, Barnett, Chow, Ramesha, and Browner, xe2x80x9cFlexibility of the NSAID Binding Site in the Structure of Human Cyclooxygenase-2xe2x80x9d, Nature Structural Biol. (1996) Vol. 3, pp. 927-933; and Kalgutkar, Crews, Rowlinson, Garner, Seibert, and Marnett, xe2x80x9cAspirin-Like Molecules that Covalently Inactivate Cyclooxygenase-2xe2x80x9d, Science (1998, Vol. 280, pp.1268-1270; U.S. Pat. No. 5,681,964 (issued in 1997) to Ashton et al., assignors to the University of Kentucky Research Foundation, which shows conversion of indomethacin (an NSAID) into certain ester derivatives with concomitant reduction of GI irritation (see, FIG. 1 of U.S. Pat. No. 5,681,964 for the structure of the ester derivatives); and U.S. Pat. No. 5,607,966 (Parent) (issued in 1997) and U.S. Pat. No. 5,811,438 (CIP) (issued in 1998), both to Hellberg et al., assignors to Alcon Laboratories, which show conversion of various NSAIDs (such as indomethacin) into certain ester derivatives and amide derivatives (that are useful as antioxidants and inhibitors of 5-lipoxygenase), but which do not address selective COX-2 inhibition.
Moreover, although U.S. Pat. No. 3,285,908 (issued in 1966) and U.S. Pat. No. 3,336,194 (issued in 1967), both to Shen, assignor to Merck and Co., Inc., describe various secondary and tertiary amide derivatives of indomethacin, the patents fail to address COX inhibition, probably because COX inhibition (both COX-1 and COX-2) was undiscovered in the 1960""s, and thus fail to recognize that tertiary amide derivatives do not inhibit either COX-1 or COX-2. (Also, see comparison compounds 36 and 37 in Example II below.) However, U.S. Pat. No. 5,436,265 (issued in 1995) to Black et al. and U.S. Pat. No. 5,510,368 (issued in 1996) to Lau et al., both patents assigned to Merck Frosst Canada, Inc., describe, respectively, 1-aroyl-3-indolyl alkanoic acids and N-benzyl-3-indoleacetic acids as COX-2 selective inhibitors.
In the present investigation, the possibility has been explored for designing selective COX-2 inhibitors using as templates various NSAIDs (1) that are selective COX-1 inhibitors or (2) that have essentially the same inhibitory activity for both COX-1 and COX-2. These two kinds of NSAIDs are collectively referred to as NSAIDs that are not selective COX-2 inhibitors.
More particularly, analysis of the human COX-2 crystal structure complexed with zomepirac-derived selective COX-2 inhibitors indicates that the structural basis for selectivity by zomepirac-derived compounds is different from that of diarylheterocyclics. See, Luong et al. mentioned above. Unlike diarylheterocyclics, zomepirac analogs do not utilize the side pocket; instead they breech the constriction at the mouth of the COX active site occupied by Arg106 and Tyr341 and project down the lobby region. The projection into this sterically uncongested region in the COX-2 active site opens the possibility that making a wide range of analogs of COOH-containing drugs, such as analogs of NSAIDs, each with a different pendent functional group replacing the OH or the H of the COOH, would accomplish many purposes related to drug discovery or development. For example, certain pendent groups could improve water-solubility, bioavailability, or pharmacokinetics. Another possibility would be to attach a pendent pharmacophore in order to target a completely different protein leading to compounds with dual pharmacological functions.
Abbott Laboratories and Parke-Davis have attempted the pharmacophore approach. See, respectively, Kolasa, Brooks, Rodriques, Summers, Dellaria, Hulkower, Bouska, Bell, and Carter, xe2x80x9cNonsteroidal Anti-Inflammatory Drugs as Scaffolds fort he Design of 5-Lipoxygenase Inhibitorsxe2x80x9d, J. Med. Chem. (1997) Vol. 40, pp. 819-824; and Flynn, Capiris, Cetenko, Connor, Dyer, Kostlan, Niese, Schrier, and Sircar, xe2x80x9cNonsteroidal Antiinflammatory Drug Hydroxamic Acids. Dual Inhibitors of Both Cyclooxygenase and 5-Lipoxygenasexe2x80x9d, J. Med. Chem. (1990) Vol. 33, pp. 2070-2072. Both Kolasa et al. and Flynn et al. reported that replacement of the carboxylic acid group in NSAIDs with a hydroxamic acid moiety or a hydroxyurea moiety provided dual inhibitors of COX and 5-lipoxygenase. Nevertheless, none of the analogs displayed any significant selective COX-2 inhibition, and furthermore the hydroxamates underwent facile hydrolysis.
Additionally, it is interesting to note that sulindac sulfide (an NSAID which contains a COOH moiety as well as a methyl sulfide moiety) is a 40-fold more potent inhibitor against COX-1 than against COX-2. On the other hand, a derivative, namely sulindac sulfone (which contains a COOH moiety as well as a methyl sulfone moiety) does not inhibit either COX-1 or COX-2.
However, nothing in the above-discussed literature suggests that converting a COOH-containing NSAID that is not selective for COX-2 inhibition into an ester derivative or a secondary amide derivative would result in a derivative that is selective for COX-2 inhibition. Thus, it would be desirable to find certain COOH-containing drugs, such as NSAIDs, which are not selective COX-2 inhibitors (either display an inhibition for COX-1 far exceeding inhibition of COX-2 or display essentially the same inhibition for COX-1 and COX-2) that would, when converted into certain derivatives, become selective COX-2 inhibitors (display an inhibition for COX-2 far exceeding inhibition for COX-1), as well as retain the analgesic, antiinflammatory, and/or antipyretic effect of the drug, such as the NSAID, prior to derivatization.
Surprisingly with the present invention, it has been found that derivatization of the carboxylic acid moiety or the pharmaceutically acceptable salt of the moiety of various compounds (for instance, of certain NSAIDs) that are not selective COX-2 inhibitors, such as indomethacin, to ester analogs or to secondary amide analogs creates isozyme specificity for COX-2. Moreover, the resultant ester derivative or secondary amide derivative is not only a selective COX-2 inhibitor, but also retains the analgesic, antiinflammatory, and/or antipyretic effect of the compound, i.e., the NSAID.
Therefore, the present invention provides a method of altering specificity of a cyclooxygenase-inhibiting compound, the method comprising the steps of:
(a) providing a compound having cyclooxygenase inhibitory activity, the compound having a carboxylic acid moiety or pharmaceutically acceptable salt thereof associated with the cyclooxygenase inhibitory activity and the compound being absent specificity for cyclooxygenase-2 inhibitory activity; and
(b) altering the specificity of the compound in step (a) from being absent specificity for cyclooxygenase-2 inhibitory activity to having specificity for cyclooxygenase-2 inhibitory activity by converting the compound having the carboxylic acid moiety or pharmaceutically acceptable salt thereof into a derivative having an ester moiety or a secondary amide moiety.
Hence, it is an object of the invention to provide a derivative drug that minimizes or obviates GI irritation. Moreover, it is an advantage of the present invention that the derivative drug is also analgesic, antiinflammatory, and/or antipyretic, absent the concomitant administration of the non-derivatized drug or a pharmaceutically acceptable salt of the non-derivatized drug.
Some of the objects of the invention having been stated above, other objects will become evident as the description proceeds, when taken in connection with the Laboratory Examples as described below.
The present invention involves a method for converting a drug into a COX-2 selective inhibitor and also for using that COX-2 selective inhibitor for treating an animal that is a warm-blooded vertebrate. Therefore, the invention concerns mammals and birds.
Contemplated is the treatment of mammals such as humans, as well as those mammals of importance due to being endangered (such as Siberian tigers), of economical importance (animals raised on farms for consumption by humans) and/or social importance (animals kept as pets or in zoos) to humans, for instance, carnivores other than humans (such as cats and dogs), swine (pigs, hogs, and wild boars), ruminants (such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels), and horses. Also contemplated is the treatment of birds, including the treatment of those kinds of birds that are endangered, kept in zoos, as well as fowl, and more particularly domesticated fowl, i.e., poultry, such as turkeys, chickens, ducks, geese, guinea fowl, and the like, as they are also of economical importance to humans. Thus, contemplated is the treatment of livestock, including, but not limited to, domesticated swine (pigs and hogs), ruminants, horses, poultry, and the like.
More particularly, a treatment effective amount of an ester derivative or a secondary amide derivative of a carboxylic acid-containing drug, such as a derivative of an NSAID, is administered to the warm-blooded vertebrate animal. Thus, the invention comprises administration of the derivative in concentrations calculated to provide the animal being treated with the appropriate milieu to provide an analgesic, antiinflammatory, or antipyretic effect.
By carboxylic-acid containing drug (such as an NSAID) or COOH-containing drug (such as an NSAID) as used herein in connection with the present invention, it is intended to include pharmaceutically acceptable acid salts of the drug. Thus, for instance, the COOH moiety includes COOM, where M is Na and the like.
The preferred derivative compounds useful in the method of the present invention are secondary amide derivatives and ester derivatives of non-steroidal antiinflammatory drugs having a carboxylic moiety or a pharmaceutically acceptable salt thereof. Various chemical classes of NSAIDs have been identified and are listed in CRC Handbook of Eicosanoids: Prostaglandins, and Related Lipids, Vol. II, Drugs Acting Via the Eicosanoids, pages 59-133, CRC Press, Boca Raton, Fla. (1989). Hence, the NSAID may be chosen from a variety of chemical classes including, but not limited to, fenamic acids, such as flufenamic acid, niflumic acid, and mefenamic acid; indoles, such as indomethacin, sulindac, and tolmetin; phenylalkanoic acids, such as suprofen, ketorolac, flurbiprofen, and ibuprofen; and phenylacetic acids, such as diclofenac. Further examples of NSAIDs are listed below:
More specifically, preferred ester derivatives and secondary amide derivatives useful in the present invention include, but are not limited to, ester derivatives and secondary amide derivatives of the following COOH-containing NSAIDs: 6-methoxy-xcex1-methyl-2-naphthylacetic acid (and its Na acid salt form known as naproxen), meclofenamic acid, and diclofenac, with ester derivatives and secondary amide derivatives of indomethacin being preferred. Also, the ester derivatives and the secondary amide derivatives of indomethacin, where the Cl at the 4-position of the benzoyl moiety is replaced with Br or F, should work in the present invention. Even more preferred are the secondary amide derivatives of indomethacin including, but not limited to, indomethacin-N-methyl amide, indomethacin-N-ethan-2-ol amide, indomethacin-N-octyl amide, indomethacin-N-nonyl amide, indomethacin-N-(2-methylbenzyl) amide, indomethacin-N-(4-methylbenzyl) amide, indomethacin-N-((R)-,4-dimethylbenzyl) amide, indomethacin-N-((S)-,4-dimethylbenzyl) amide, indomethacin-N-(2-phenethyl) amide, indomethacin-N-(4-fluorophenyl) amide, indomethacin-N-(4-chlorophenyl) amide, indomethacin-N-(4-acetamidophenyl) amide, indomethacin-N-(4-methylmercapto)phenyl amide, indomethacin-N-(3-methylmercaptophenyl) amide, indomethacin-N-(4-methoxyphenyl) amide, indomethacin-N-(3-ethoxyphenyl) amide, indomethacin-N-(3,4,5-trimethoxyphenyl) amide, indomethacin-N-(3-pyridyl) amide, indomethacin-N-5-((2-chloro)pyridyl) amide, indomethacin-N-5-((1-ethyl)pyrazolo) amide, indomethacin-N-(3-chloropropyl) amide, indomethacin-N-methoxycarbonylmethyl amide, indomethacin-N-2-(2-L-methoxycarbonylethyl) amide, indomethacin-N-2-(2-D-methoxycarbonylethyl) amide, indomethacin-N-(4-methoxycarbonylbenzyl) amide, indomethacin-N-(4-methoxycarbonyl methylphenyl) amide, indomethacin-N-(2-pyrazinyl) amide, indomethacin-N-2-(4-methylthiazolyl) amide, indomethacin-N-(4-biphenyl) amide, and combinations thereof.
The ester derivative or the secondary amide derivative may be administered to the animal as a suppository or as a supplement to fluids that are administered internally or parenterally, for instance nutriment fluids such as intervenous sucrose solutions. Furthermore, intraoral (such as buccal or sublingual) administration or transdermal (such as with a skin patch) administration to the animal is also contemplated. A good discussion of intraoral administration can be seen in U.S. Pat. No. 4,229,447 issued Oct. 21, 1980 to Porter and U.S. Pat. No. 5,504,086 issued Apr. 2, 1996 to Ellinwood and Gupta. A good discussion of transdermal administration can be seen in U.S. Pat. No. 5,016,652 issued May 21, 1991 to Rose and Jarvik.
Additionally, administration to the animal may be by various oral methods, for instance as a tablet, capsule, or powder (crystalline form) that is swallowed. Also, oral administration may include that the ester derivative or the secondary amide derivative is admixed in a carrier fluid appropriate therefor so that it is administered as a liquid (solution or suspension) that is drunk. When the derivative is admixed in a carrier fluid, appropriate fluids include, but are not limited to, water, rehydration solutions (i.e., water with electrolytes such as potassium citrate and sodium chloride, for instance the solution available under the trade name RESOL(copyright) from Wyeth Laboratories), nutritional fluids (i.e., milk, fruit juice), and combinations thereof. Thus, the oral administration may be as a component of the diet, such as human food, animal feed, and combinations thereof.
In addition to oral administration such as by way of the mouth, contemplated also is administration of a solution or suspension to the esophagus, stomach, and/or duodenum, such as by gavage, i.e., by way of a feeding tube. Gavage type of administration is useful for when the animal is very ill and can no longer swallow food, medicine, et cetera, by mouth.
Hence, it is also contemplated that additional ingredients, such as various excipients, carriers, surfactants, nutriments, and the like, as well as various medicaments, other than the ester derivative or other than the secondary amide derivative, or combinations thereof, may be present together with the derivative, whatever the form that the derivative is in. Medicaments other than an ester derivative or a secondary amide derivative may include, but are not limited to, osmolytic polyols and osmolytic amino acids (i.e., myo-inositol, sorbitol, glycine, alanine, glutamine, glutamate, aspartate, proline, and taurine), cardiotonics (i.e., glycocyamine), analgesics, antibiotics, electrolytes (i.e., organic or mineral electrolytes such as salts), and combinations thereof.
A suitable dosing amount of ester derivative or secondary amide derivative for administration to the animal should range from about 0.5 mg to about 7.0 mg per kg of body weight of the animal per day, more preferably from about 1.5 mg to about 6.0 mg per kg of body weight of the animal per day, and even more preferably from about 2.0 mg to about 5.0 mg per kilogram of body weight of the animal per day. Administration may be one or more times per day to achieve the total desired daily dose. Of course, the amount can vary depending on the severity of the illness and/or the age of the animal.
The present invention indicates that carboxylic acid-containing compounds that are not COX-2 selective inhibitors, such as the NSAID known as indomethacin, when converted into esters or into secondary amides, results in isozyme specificity for COX-2 and thus presents an efficient strategy for the generation of potent and selective COX-2 inhibitors. The below-discussed extensive SAR study conducted with indomethacin suggests that a variety of ester substituents are tolerated for replacing the H in the COOH moiety of indomethacin and that a variety of secondary amide substituents are tolerated for replacing the OH in the COOH moiety of indomethacin, and these resultant derivatives are as potent and selective as COX-2 inhibitors as are the diarylheterocyclics discussed above. Thus, this strategy has great potential in the development of nonulcerogenic antiinflammatory agents.